Abstract:
:At one time, atherosclerosis was thought to be a simple lipid storage disease. However, it is now recognized as a chronic and progressive inflammation of the arterial wall. Gene deletion experiments in murine models of atherosclerosis that reduce the inflammatory process also reduce disease severity. Identifying the initiators and mediators of that inflammation can provide promising avenues for prevention or therapy. Two prominent risk factors, hyperlipidemia and infectious disease, point to innate immune mechanisms as potential contributors to proatherogenic inflammation. The Toll-like receptors (TLR), proinflammatory sensors of pathogens, are potential links between inflammation, infectious disease and atherosclerosis. There is increasing evidence that TLRs also recognize host-derived ligands and this also connects TLRs to diseases that may not have an etiology that is associated directly with infection. A mechanism for hyperlipidemic initiation of sterile inflammation can be postulated because oxidized lipoproteins or their component oxidized lipids have been identified as TLR ligands. Moreover, infectious agents are correlated with atherosclerosis risk. There are multiple published reports that TLR4 activation is relevant to the inflammation of atherosclerosis in mice and humans. In addition, we have identified a role for TLR2 in atherosclerosis in low density lipoprotein receptor-deficient (LDLr-/-) mice. Proatherogenic TLR2 responses to unknown endogenous or unknown endemic exogenous agonists are mediated by non-bone marrow-derived cells, which can include endothelial cells, adventitial fibroblasts and vascular smooth muscle cells. This is in contrast to the proatherogenic TLR2 response to defined synthetic exogenous agonists, which is mediated at least in part by bone marrow-derived cells, which can include lymphocytes, monocytes/macrophages, NK cells and dendritic cells. Thus, TLR2-mediated cell activation in response to endogenous and exogenous agents is proatherogenic in hyperlipidemic mice.
journal_name
Curr Drug Targetsjournal_title
Current drug targetsauthors
Curtiss LK,Tobias PSdoi
10.2174/138945007783220605subject
Has Abstractpub_date
2007-12-01 00:00:00pages
1230-8issue
12eissn
1389-4501issn
1873-5592journal_volume
8pub_type
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journal_title:Current drug targets
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